This proposal sets in motion a 3 year plan to study the protein network involved in the pathogenesis of Spinal Muscular Atrophy (SMA), as well as establish the applicant as an independent investigator. The applicant has spent the last 8 years preparing for a career as an academic neuropathologist through his previous Ph.D. experience, which focused on mechanisms of neurodegeneration, and through clinical residency training in Anatomic Pathology and Neuropathology. The career development proposed in this application will complement his previous experience, which lacked exposure to biochemistry and advanced molecular biology, and provide him with the proper technical skills and intellectual framework to enable him to study pediatric neurodegenerative diseases. The applicant has chosen Dr. Gideon Dreyfuss as his sponsor. Dr. Dreyfuss is a recognized authority in the field of mRNA processing and a pioneer in the study of pediatric neurological diseases caused by aberrant RNA metabolism, including SMA and the Fragile-X syndrome. SMN (for Survival of Motor Neuron), the gene responsible for SMA, plays a critical role in spliceosomal. biogenesis and in pre-mRNA splicing, as first demonstrated by the sponsor's lab. However, the precise function of SMN is unknown. SMN is in a complex with several proteins. The applicant hypothesizes that by isolating and functionally characterizing these proteins he may uncover the molecular mechanism(s) of SMN function. In addition by studying the association of SNIN mutants, found in SMA patients, with these proteins he may uncover defective interactions which would help elucidate the molecular pathogenesis of SMA. Finally, by analyzing the composition of the SMN complex in neuronal cell lines he may uncover neuronal targets for SMN.